Alopecia areata (AA) affects approximately 4.6 million individuals in the United States alone, including males and females of all ages and ethnic groups, it is typified by patchy hair loss on the scalp that can progress to cover the entire scalp (alopecia totalis), and eventually the entire body (alopecia universalis). Despite its high incidence, the genetic basis of AA is largely unknown. An autoimmune mechanism has been postulated for many years, however an auto-antigen has never been identified. Although it is now generally accepted that AA fits the paradigm of a complex or multifactorial trait, in which a combination of genetic and environmental factors combine to result in the final phenotype, they have received little attention. Genetic studies have been limited to association analyses, which suggest that a permissive HLA status may potentiate the development of the AA phenotype. However, a systematic screen for identifying the primary genetic mechanisms underlying this disorder has never before been undertaken. In this grant application we propose comprehensive genetic analysis of AA by performing a genome-wide scan in AA multiplex pedigrees. We thoroughly address three key aspects critical to the design of the genetic dissection of a complex trait, namely, the ascertainment of families, the genome-wide scans, and finally, the application of statistical analysis of the genotype data obtained. For the first time, the technology for the comprehensive genetic analysis of polygenic diseases such as AA is now readily available. There are currently a number of examples of complex diseases of the skin, such as atopic dermatitis and psoriasis, in which genetic studies are being undertaken that substantiate the timeliness of this approach. We anticipate these studies will lead to the identification of AA susceptibility genes. They will provide a foundation for understanding the interactions of this gene(s) with each other and with other variables such as the immune system and environmental factors, and ultimately illuminate therapeutic targets for the future.